Grant: Project Grant

After severe skin injury such as burns our body rapidly but poorly repairs the damage, leaving behind stiff scar tissue. Scarring is a clinical burden because skin is losing vital functions. During normal repair, skin fibroblasts are transiently activated into myofibroblasts (MF) to secrete and organize fibrous collagen. This action prevents our tissues from breaking. However, MF produce debilitating hypertrophic scars when MF persist and keep accumulating collagen. To support normal healing and reduce scarring, mesenchymal stromal cells (MSC) are tested in clinical trials. MSC can and help regenerating injured organs by modulating the wound healing process after transplantation. MSC are obtained from donor biopsies and are multiplied in cell culture to obtain millions of MSC required for a therapy. This is a problem because the conditions of cell culture turn MSC into persistent MF, which may worsen scarring after transplantation to wounds. We published that expansion on conventional stiff plastic culture surfaces activates MSC into scar MF. Instead, prolonged 'priming' of MSC on 'skin-soft' polymer surfaces suppresses MF activation and preserves regenerative MSC. These features were memorized even after subsequent exposure to scar-stiff culture environment and transplantation to animal models of scar wound healing. We hypothesize that mechanical environment imprints memory by inducing stable DNA modifications. We will analyze such 'epigenetic' alterations in mechanically primed MSC and link them to the expression of scar-promoting and -suppressing genes. We will identify 'memory keepers' that will be chemically and genetically manipulated to create desired memory in MSC. These MSC will then be tested in transplant animal models to improve wound healing by resisting persistent MF activation and preserving regeneration. Understanding and controlling the mechanisms of MSC activation into scar cells will augment the success rate of tissue regeneration therapies.